Mineralocorticoid Receptor Blockade Attenuates Proliferative Changes in the Rat Pulmonary Artery in Monocrotaline-Induced Pulmonary Hypertension
Monocrotaline誘発肺高血圧ラットにおける肺小動脈リモデリング形成過程におけるMineralocorticoid receptor 拮抗剤eplerenoneの効果

Kan Hamori, Shintaro Nemoto, Tomoyasu Sasaki, Takahiro Katsumata, Kanta Kishi, Kennici Okumura, Noriyasu Ozaki, Hirosi Katayama
2014 Pediatric Cardiology and Cardiac Surgery  
Pulmonary hypertension, Aldosterone, Mineralocorticoid receptor, Eplerenone 羽森 貫 1) ,根本慎太郎 2) ,佐々木智康 3) ,勝間田敬弘 3) , 岸 勘太 4) ,奥村 謙一 4) ,尾崎 智康 4) ,片山 博視 4) 大阪医科大学附属病院リハビリテーション医学 1) ,小児心臓血管外科 2) , 心臓血管外科 3) ,小児科学 4) Background: Pulmonary arterial hypertension (PAH) is recognized as a spectrum of pulmonary vascular remodeling that leads to lumen obstruction induced by a nexus of unregulated proliferative signaling. We hypothesized that mineralocorticoid receptor (MR) signaling plays a significant
more » ... le in the remodeling, and that antagonizing MR could ameliorate the vascular impairments in PAH. Methods: Male rats were divided into two groups one day after a single subcutaneous injection of monocrotaline (60 mg/kg) : one group received oral eplerenone (EPL, 100 mg/kg per day, N = 6) and the other received vehicle (N = 8) . Animals in another group with saline injection and no medication served as control (N = 8) . After three weeks of treatment, right ventricular (RV) function was assessed and RV pressure was measured. The mRNA levels for the MR, angiotensin II type 1a receptor and transforming growth factor-β 1 in the lungs were measured by quantitative RT-PCR. Results: Peak RV pressure was significantly higher in the vehicle group compared to the control but significantly reduced in the EPL group (p < 0.01) . RV function (Tei-index) was significantly reduced in the vehicle group compared to the control but significantly preserved in the EPL group (p < 0.01) . The eplerenone group showed significantly greater reduction in % medial wall thickness of pulmonary arterioles compared to the vehicle group (20.7 ± 7.4 vs. 43.5 ± 7.5, p < 0.01) . All mRNA levels were significantly upregulated in the vehicle group, compared to the control. Eplerenone treatment resulted in significant reduction in these mRNA levels, compared to the vehicle group (p < 0.01) . Conclusions: These results suggest that MR signaling plays at least a partial role in the proliferative vascular remodeling of PAH and that MR blockade may be an effective alternate treatment for PAH. 要 旨 肺高血圧症の病態の本質は肺動脈リモデリングである.しかし,肺高血圧症における aldosterone 系のリモデリン グへの関与は明らかでない.本研究では monocrotaline 誘発肺高血圧ラットを用い,肺動脈リモデリングにおける aldosterone 系の関与を検討した.加えて monocrotaline 投与の翌日からの選択的 mineralocorticoid receptor 拮抗薬 (eplerenone) による治療介入を行い,病態形成への有効性を比較・評価した.正常コントロールに比し,無治療肺高 血圧群で生じた右心室圧の著しい上昇と右心室機能障害は eplerenone 投与群では有意に抑制された.組織学的には 無治療群で顕著であった肺小動脈での中膜肥厚と筋性化は eplerenone 投与群で有意に抑制された.無治療群の肺組 織で上昇した mineralocorticoid receptor,angiotensin-1a receptor,transforming growth factor-β 1 の各 mRNA の発現は 2013 年 8 月 12 日受付 2014 年 4 月 28 日受理 別刷請求先:〒 569-8686 大阪府高槻市大学町 2-7 大阪医科大学外科学講座胸部外科学教室 根本慎太郎 平成26年7月1日 65 PEDIATRIC CARDIOLOGY and CARDIAC SURGERY VOL.30 NO.4 (438-447) 原 著 eplerenone 投与群では有意に抑制された.以上より monocrotaline 誘発肺高血圧ラットの肺動脈リモデリング過程お いて,aldosterone 系の関与が強く示唆された.加えて eplerenone 投与がこのリモデリングを抑制する有効な治療とし ての可能性も示唆された. 日本小児循環器学会雑誌 第30巻 第4号 66 439
doi:10.9794/jspccs.30.438 fatcat:qofwd2754vcs7b3j5sldvgxbxq